CA2077031A1 - Process for the resolution of enantiomers of 5-heteroaryl-1,3,4-thiadiazinones - Google Patents

Process for the resolution of enantiomers of 5-heteroaryl-1,3,4-thiadiazinones

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Publication number
CA2077031A1
CA2077031A1 CA002077031A CA2077031A CA2077031A1 CA 2077031 A1 CA2077031 A1 CA 2077031A1 CA 002077031 A CA002077031 A CA 002077031A CA 2077031 A CA2077031 A CA 2077031A CA 2077031 A1 CA2077031 A1 CA 2077031A1
Authority
CA
Canada
Prior art keywords
resolution
enantiomers
diastereoisomers
methyl
mixture
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002077031A
Other languages
French (fr)
Inventor
Rochus Jonas
Peter Ersing
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck Patent GmbH
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2077031A1 publication Critical patent/CA2077031A1/en
Abandoned legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

Abstract of the Disclosure The invention relates to a process for the resolution of enantiomers of 5-heteroaryl-1,3,4-thiadiazinones of formula I by the kinetic resolution of racemates, characterised in that racemic I is dissolved in an inert solvent or solvent mixture and acylated with a chiral acid chloride, the resulting mixture of diastereoisomers is reacted with an amine, thereby achieving a complete resolution of one of the diastereoisomers and a very slight resolution of the other diastereoisomer into the enantiomers on which they are based, the resolution products are then separated off and the remaining pure diastereoisomer is converted to the corresponding pure enantiomer by reaction with an amine or an alcohol.

Description

- 2 - 2~7~
Merck Patent Ge~ellschaft mit beschrankter ~aftung 6100 D a r m 8 t a d t Process for the re~olution of enantiomers of 5-heteroaryl-1,3,4-thiadiazinones The invention relates to a proces~ for the resolution of enantiomers of S-heteroaryl-l,3,4-thia-diazinones of formula I:

(CH~ cO

R~

10 wherein Rl is A, : RZ and R3 are each ~ or A, R4 is H, A or acyl having 1-15 C atoms, A is alkyl having 1-8 C atoms and n i8 1, 2 or 3.
Thiadiazinone derivatives of formula I are known from European patent 0 294 647 and have the meanings indicated therein a~ preferred.
Above and below, R1 to R4 and A are as defined for formula I, unless expressly indicated otherwi~e.
In the formulae, alkyl is preferably unbranched, has preferably 1, 2 or 3 C atoms and is preferably methyl, or preferably ethyl or propyl, or else preferably isopropyl, butyl, isobutyl, sec-butyl, tert- butyl, n-.. .

. ~ ~ - ; ,, .
, ~ -, 2 ~7 pentyl or isopentyl.
Acyl is the acid radical of a carboxylic or sulfonic acid, preferably alkanoyl having 1-10 or especially 1, 2, 3, 4 or 5 C atoms, specifically preferably acetyl, or preferably formyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl or pivaloyl (trimethylacetyl)~ or el~e preferably substituted or unsubstituted aroyl having 7-15 C atoms, po~sible substituents being especially 1-3 or preferably one of the following groups: alkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl each having 1-3 or preferably 1 or 2 C atoms, methylenedioxy and also OH, F, Cl, Br, I, NO2, NH2 and alkylamino or dialkylamino each having 1-3 or preferably 1 or 2 C atoms in the alkyl group. Specific preferred aroyl radicals are benzoyl, o-, m- or p- toluyl, o-, m- or p-methoxybenzoyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzoyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- or 3,4,5-trimethoxy-benzoyl, o-, m- or p-methy}thiobenzoyl, o-, m- or p-methylsulfinylbenzoyl, o-, m- or p-methylsulfonylbenzoyl, 2,3- or 3,4-methylenedioxybenzoyl and 1- or 2-naphthoyl.
Acyl can also be heteroarylcarbonyl having 2-10 C atoms, such as 2- or 3-furoyl, 2- or 3-thenoyl, picolinoyl, nicotinoyl or isonicotinoyl, or else arylalkanoyl such as phenylacetyl, o-, m- or p-methoxyphenylacetyl, 2- or 3-phenylpropionyl or 2-, 3- or 4-phenylbutyryl, cycloalkyl-carbonyl such as cyclohexylcarbonyl, alkylsulfonyl such as methyl-, ethyl-, propyl- or butyl-sulfonyl, or aryl-sulfonyl such as benzenesulfonyl, o-, m- or p- toluene-sulfonyl, o-, m- or p-methoxybenzenesulfonyl or 1- or 2-naphthalenesulfonyl.
Re~olution of the racemate into the respective enantiomers has hitherto been possibl~ only by means of expensive HPLC processes.
The object of the invention was to provide a proce~s for the resolution of enantiomers of I which avoid~ an expensive ~PLC re~olution with a small through-put of ~ubstance, but simultaneously produces a high .. . . .
- :

. -. .
.
, - 4 - 2~7~
enantiomeric purity in satisfactory amounts of sub~tance.
This object was achieved by the discovery of the present process, namely the kinetic resolution of race-mates, in respect of the resolution of enantiomers of 5-heteroaryl-1,3,4-thiadiazinones.
The invention accordingly relates to a process for the resolution of enantiomers of I, characterised in that racemic I is dissolved in an inert solvent or solvent mixture and acylated with a chiral acid chloride,`the resulting mixture of diastereoisomers i8 reacted with an amine or alcohol, thereby achieving a complete resolution of one of the diastereoisomers and a -very slight resolution of the other diastereoisomer into the enantiomers on which they are based, the resolution products are then separated off and the remaining pure diastereoisomer is converted to the corresponding pure -enantiomer by reaction with an amine or an alcohol.
The process of the kinetic resolution of racemates does not normally produce a satisfactory enantiomeric purity and has to be supplemented by addi-tional processes.
It is therefore surprising that this process can be~applied successfully in the case of I and produces an enantiomeric purity of more than 99% in all Examples without the use of supplementary methods.
Suitable solvents are preferably ethers such as tetrahydrofuran (T~F), dioxane or methyl tert.-butyl ether, hydrocarbon~ such as hexane, cyclohexane, benzene, toluene, xylenes or mesitylene, glycol dialkyl ethers such as glycol dimethyl or diethyl ether, amides such as dimethylformamide ~DMF), halogenated hydrocarbon~ ~uch a8 methylene chloride, chlorobenzene or trichloroethylene, and mixtures of these solvents.
Methylene chloride and THF are particularly preferred.
Examples of suitable optically active acid chlo-rides are tetrahydro-5-oxofuran-2-carboxylic acid chlo-ride, o-acetylmandelic acid chloride, campholic acid .
:, - . .
.
- -:

,:
: ' ' ' .

2~ 3~L

chloride or, particularly preferably, camphanic acid chloride.
Specifically, racemic I i8 dissolved or suspended in one of said solvents or a solvent mixture, a base is conveniently added and the acid chloride, dissolved in one of said solvents or in the pure form, i~ added.
Examples of suitable bases are alkali metal or alkaline earth metal hydroxides, carbonates and alcoholates, but especially secondary or tertiary amine~ such as, for example, triethylamine or pyridine.~The reaction mixture is then stirred for 1-48 hours at temperatures of between -20 and the boiling point of the solvent, preferably in the range from -10 to +30, and the mixture of diastereoisomers is isolated. To resolve the mixture of diastereoisomer~, said mixture is ~edissolved in one of said solvents, treated with an amine or an alcohol and again stirred for 1-48 hours at 0-50, preferably at 0-30, or simply lef~ to stand.
It is equally pos~ible to dissolve the mixture of diastereoisomers directly in a suitable alcohol without using an additional solvent.
Examples of suitable alcohols are lower alcohols having 1-8 C atoms, especially methanol, ethanol or isopropanol, but also mixtures thereof. Suitable amines 25~ are inter alia piperidine, pyrrolidine, morpholine or else ethylamine.
In the following Bxamples, which serve to illustrate the invention in greater detail, all temperatures are given in C, as in the preceding text.
"Conventional working-up~ mean~ that water or dilute sodium hydroxide solution io added if neces~ary, the mixture i~ extracted with an organic solvent such as ethyl acetate, chloroform or methylene chloride, the organic phase is separated off, dried over Na2S0~ or MgS0~, filtered and evaporated and the residue is additionally purified by chromatography or crystallisation if appropriate. The enantiomeric purity can be determined for example by HPLC or differential ,. -, ' ~, "' '.

scanning calorimetry (DSC). The abbreviations HPLC and ee ~tand for high pressure liquid chromatography and enantiomeric excess.

~xample 1 A 301ution of 26 g of (-)-camphanic acid chloride in 100 ml of methylene chloride is added dropwise at 0, with stirring, to a suspension of 48 g of 5-[1- (3,4-methylenedioxybenzoyl)-1,2,3,4-tetrahydroquino~-6- yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one in 800 ml of methylene chloride to which 20 ml of triethylamine have been added, and the reaction mixture is stirred for 4 hours. It i8 then washed with dilute hydrochloric acid and sub~equently with bicarbonate solution. The organic phase is separated off and worked up in conventional manner to give 3-[(-)-camphanoyl]-5-~1-(3,4-methylenedioxybenzoyl)-1,2,3,4- tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4- thiadiazin-2-one as a mixture of diastereoisomers, m.p. 216-217.

Example 2 48 g of the mixture of diastereoi~omers of Example 1 are dissclved in 800 ml of tetrahydrofuran, 3.6 ml of morpholine are added and the reaction mixture is left to stand for 14 hours at 25. It is concentrated, aqueous ethyl acetate is added and the mixture is worked up in conventionaI manner. The (-)-enantiomer obtained by re~olution, which is contaminated with small amounts of (+)-enantiomer, i9 separated from the bulk of the unresolved diastereoisomer by chromatography. ~he small amount of ~+)-enantiomer present is removed from the (-)-enantiomer as the racemate by recrystallisation from ethanol. Concentration of the mother liquor and crystal-lisation gives (-)-5-[1-(3,4- methylenedioxybenzoyl)-1,2,3,4-tetrahydroquinol-6-yl]- 6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, m.p. 180; [~] D20 - -534.2; ee >
99% (HPLC~.

_ 7 - 2~
~xample 3 20 g of the unresolved diastereoisomer of Example 2 are dissolved in THF, 3 ml of morpholine are added and the mixture is processed further analogously to Example 2. After removal of the solvent, the residue i8 recrystalli~ed from ethanol to give (+)-5-[1- (3,4-methylenedioxybenzoyl)-1,2,3,4-tetrahydroquinol-6- yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, m.p. 181; ~]D20 ~ +541.5; ee > 99%.

Example 4 20 g of the unresolved diastereoisomeric compound of Example 2 are dissolved in 400 ml of methanol and boiled for 24 hours. After removal of the solvent, the residue is recrystallised from ethanol to give (+)- 5-tl-(3,4-methylenedioxybenzoyl)-1,2,3,4-tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, m.p. 181; [~]D20 - +541.5; ee > 99%.

xa-ple 5 Analogously to Example 1, the racemic mixture of 5-tl-methyl-1,2,3,4-tetrahydroquinol-6-yll-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one (m.p. 177) is reacted with (+)-camphanic acid chloride to give 3- 1(+)-camphanoyl]-5-(1-methyl-1,2,3,4-tetrahydroquinol- 6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one as a mixture of diastereoisomers.

Example 6 The mixture of diastereoisomors of Example 5 is reacted with morpholine analogously to Example 2 to give (+)-5-(1-methyl-1,2,3,4-tetrahydroquinol-6-yl)-6- methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one and the corresponding unresolved diastereoisomer, the further processing of which is described in Example 7.

.- .. ~ ........ :

.
. . ';~

2~
Example 7 The unresolved diastereoisomer of Example 6 is dissolved in methanol and boiled for 20 hours, analogously to Example 4. After removal of the solvent, S the residue is recrystallised from ethanol to give (-)-5-(1-methyl-1,2,3,4-tetrahydroguinol-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one.

E~a~ple 8 Analogously to Example 1, the racemate of S-~1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one is reacted with (-)-camphanic acid chloride to give 3-t(+)-camphanoyl]-5-tl-(3,4,5-trimethoxybenzoyl)- 1,2,3,4-tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H- 1,3,4-lS thiadiazin-2-one as a mixture of diastereoisomers.
3-t(+)-Camphanoyl]-S-tl-isonicotinoyl-2,3,4,5-tetrahydro-lH-l-benzazepin-7-yl]-6~methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one is obtained analoqously.

xa ple 9 The mixture of diastereoisom rs of Example 8 i~
reacted with morpholine analogou~ly to Example 2 to give (-)-S-tl-(3,4,5-trimethoxybenzoyl)-1,2,3,4-tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one and the corresponding unresolved diastereoisomer, the further processing of which is doscriSed in Example 10.
(-)-5-[1-Isonicotinoyl-2,3,4,5-tetrahydro-lH-1-benzazepin-7-yl]-6-methyl-3~6-dihydro-2H-1~3,4-thiadiazin-2-ono is obtained analogou~ly.

~x~æle 10 Analogously to Example 3, (+)-5-tl-(3~4~5-trimethoxybenzoyl)-1,2,3,4-tetrahydroquinol-6-yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadia~in-2-one, 1~]D2C
+476.2, is obtained starting from the unresolved dia~tereoisomer of Example 9.

.

;~7'~3~.
(+)-5-[1-Isonicotinoyl-2,3,4,5-tetrahydro-1~

benzazepin-7-yl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, [~]D = +478.2, ig obtained analogously.

Claims (2)

1. A process for the resolution of enantiomers of 5-heteroaryl-1,3,4-thiadiazinonas of formula I:

I

wherein R1 is A, R2 and R3 are each H or A, R4 is H, A or acyl having 1-15 C atoms, A is alkyl having 1-8 C atoms and n is 1, 2 or 3, by the kinetic resolution of racemates, characterised in that racemates of the compounds of formula I are dissolved in an inert solvent or solvent mixture and acylated with a chiral acid chloride, the resulting mixture of diastereoisomers is reacted with an amine, thereby achieving a complete resolution of one of the diastereoisomers and a very slight resolution of the other diastereoisomer into the enantiomers on which they are based, the resolution products are then separated off and the remaining pure diastereoisomer is converted to the corresponding pure enantiomer by reaction with an amine.
2. A process according to Claim 1, characterised in that alcohols are used for resolving the diastereoisomers.
CA002077031A 1991-09-02 1992-08-31 Process for the resolution of enantiomers of 5-heteroaryl-1,3,4-thiadiazinones Abandoned CA2077031A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4129062A DE4129062A1 (en) 1991-09-02 1991-09-02 METHOD FOR ENANTIOMER SEPARATION OF 5-HETARYL-1,3,4-THIADIAZINONES
DEP4129062.3 1991-09-02

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CA2077031A1 true CA2077031A1 (en) 1993-03-03

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US (1) US5206363A (en)
EP (1) EP0530657B1 (en)
JP (1) JPH05202041A (en)
KR (1) KR930006016A (en)
AT (1) ATE144982T1 (en)
AU (1) AU658215B2 (en)
CA (1) CA2077031A1 (en)
CZ (1) CZ281376B6 (en)
DE (2) DE4129062A1 (en)
DK (1) DK0530657T3 (en)
ES (1) ES2095992T3 (en)
GR (1) GR3022443T3 (en)
HU (1) HU212178B (en)
MX (1) MX9204972A (en)
NO (1) NO300498B1 (en)
PL (1) PL169606B1 (en)
RU (1) RU2053231C1 (en)
SK (1) SK278678B6 (en)
TW (1) TW234113B (en)
ZA (1) ZA926617B (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19500558A1 (en) * 1995-01-11 1996-07-18 Merck Patent Gmbh 3-alkoxycarbonyl-thiadiazinones
DE19707641C1 (en) * 1997-02-26 1998-03-26 Merck Patent Gmbh Chromatographic separation of hetero:aryl-thiadiazinone derivatives
DE19929785A1 (en) 1999-06-29 2001-01-04 Bayer Ag Tetrahydroquinolinyl-6-methyldihydrothiadiazinon derivatives and their use
US20030153585A1 (en) * 2000-01-13 2003-08-14 Sven-Alexander Schreder Pharmaceutical preparations containing 2-pyrrolidone as the dissolving intermediary
US7741317B2 (en) * 2005-10-21 2010-06-22 Bristol-Myers Squibb Company LXR modulators

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL77031A (en) * 1985-11-12 1995-12-08 Yeda Res & Dev Kinetic resolution of racemic mixtures by polymer-bound crystallization inhibitors
US4716246A (en) * 1986-08-22 1987-12-29 Merck & Co., Inc. Process for L-dopa
AU614965B2 (en) * 1987-06-06 1991-09-19 Merck Patent Gesellschaft Mit Beschrankter Haftung Thiadiazinones

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EP0530657A1 (en) 1993-03-10
AU658215B2 (en) 1995-04-06
SK263492A3 (en) 1997-12-10
ATE144982T1 (en) 1996-11-15
JPH05202041A (en) 1993-08-10
RU2053231C1 (en) 1996-01-27
DE59207484D1 (en) 1996-12-12
US5206363A (en) 1993-04-27
DE4129062A1 (en) 1993-03-04
KR930006016A (en) 1993-04-20
SK278678B6 (en) 1997-12-10
GR3022443T3 (en) 1997-04-30
DK0530657T3 (en) 1997-04-07
ZA926617B (en) 1993-03-25
CZ263492A3 (en) 1993-03-17
HU9202806D0 (en) 1992-11-30
PL169606B1 (en) 1996-08-30
NO300498B1 (en) 1997-06-09
HUT63414A (en) 1993-08-30
PL295804A2 (en) 1993-03-08
HU212178B (en) 1996-03-28
ES2095992T3 (en) 1997-03-01
MX9204972A (en) 1993-03-01
CZ281376B6 (en) 1996-09-11
EP0530657B1 (en) 1996-11-06
AU2205192A (en) 1993-03-11
NO923412L (en) 1993-03-03
TW234113B (en) 1994-11-11
NO923412D0 (en) 1992-09-01

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FZDE Discontinued